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Abstract:

There is provided inter alia a compound of formula (I):
##STR00001##
wherein R1, J, Ar, L, X, R3 and R4 are as defined in the
specification, for use in the treatment of inflammatory disorders.

Claims:

1. A compound of formula (I): ##STR00037## wherein: J represents
##STR00038## Ar is a naphthylene or phenyl ring either of which may be
optionally substituted by one more groups independently selected from
C1-6 alkyl, C1-6 alkoxy, amino, C1-4 mono alkyl amino and
C2-8 di-alkyl amino; Q is N, or CH; R1 is H, phenyl, or a
saturated or unsaturated branched or unbranched C1-10 alkylene in
the form of an acyclic or alicyclic chain wherein one or more carbons in
the chain are optionally replaced by a heteroatom(s) independently
selected from --O--, --N-- and S(O)n and the chain is optionally
substituted by: one oxo group, and/or one or more halogen atoms; R2a
is H, halo, saturated or unsaturated branched or unbranched C1-8
alkylene chain, wherein one or more carbons are optionally replaced by a
heteroatom(s) independently selected from --O--, --N-- and/or S(O)m
and the chain is optionally substituted by one or more halogen atoms;
R2b is H, halo, C1-6 alkoxy or C1-6 alkyl optionally
substituted by OH; L is saturated or unsaturated branched or unbranched
C1-6 alkylene chain, wherein one or more carbons are optionally
replaced by a heteroatom selected from --O-- and/or S, and the chain is
optionally substituted by one or two oxo groups; X is a pyridine or
pyrimidine ring optionally substituted by C1-3 alkyl, or C1-3
haloalkyl; R3H or C1-4 alkyl; R4 is C1-10 branched or
unbranched acyclic or alicyclic alkyl chain; n is 0, 1 or 2; m is 0, 1 or
2; or a pharmaceutically acceptable salt thereof, including all
stereoisomers, tautomers and isotopic derivatives thereof.

Description:

FIELD OF THE INVENTION

[0001] The invention relates to compounds which are inhibitors of p38
mitogen-activated protein kinase enzymes (referred to herein as p38 MAP
kinase inhibitors), for example the alpha and gamma kinase sub-types
thereof, and their use in therapy, including in pharmaceutical
combinations, especially in the treatment of inflammatory diseases,
including inflammatory diseases of the lung, such as COPD.

BACKGROUND OF THE INVENTION

[0002] Four p38 MAPK isoforms (alpha, beta, gamma and delta respectively)
have been identified, each displaying a tissue-specific expression
pattern. The p38 MAPK alpha and beta isoforms are ubiquitously expressed
throughout the body and are found in many different cell types. The p38
MAPK alpha and beta isoforms are inhibited by certain known small
molecule p38 MAPK inhibitors. Earlier generations of compounds were
highly toxic due to the ubiquitous expression pattern of these isoforms
and off-target effects of the compounds. More recent inhibitors are
improved to be highly selective for p38 MAPK alpha and beta isoforms and
have a wider safety margin.

[0003] Less is known about the p38 MAPK gamma and delta isoforms. These
isoforms are expressed in specific tissues/cells (unlike the p38 alpha
and p38 beta isoforms). The p38 MAPK-delta isoform is expressed more in
the pancreas, testes, lung, small intestine and kidney. It is also
abundant in macrophages (Smith, S. J. (2006) Br. J. Pharmacol.
149:393-404) and detectable in neutrophils, CD4+ T cells and endothelial
cells (www.genecard.org, Karin, K. (1999) J. Immunol.). Very little is
known about the expression of p38 MAPK gamma but it is expressed more in
brain, skeletal muscle and heart, as well as in lymphocytes and
macrophages (www.genecard.org).

[0004] Selective small molecule inhibitors of p38 MAPK-gamma and p38
MAPK-delta are not currently available, but one existing compound, BIRB
796, is known to have pan-isoform inhibitory activity. The p38 gamma and
p38 delta inhibition is observed at higher concentrations of the compound
than those required to inhibit p38 alpha and p38 beta (Kuma, Y. (2005) J.
Biol. Chem. 280:19472-19479). BIRB 796 also impaired the phosphorylation
of p38 MAPKs or JNKs by the upstream kinase MKK6 or MKK4. Kuma discussed
the possibility that the conformational change caused by the binding of
the inhibitor to the MAPK protein may affect the structure of both its
phosphorylation site and the docking site for the upstream activator,
therefore impairing the phosphorylation of p38 MAPKs or JNKs.

[0005] p38 MAP kinase is believed to play a pivotal role in many of the
signalling pathways that are involved in initiating and maintaining
chronic, persistent inflammation in human disease, for example, in severe
asthma and COPD. There is now an abundant literature which demonstrates
that p38 MAP kinase is activated by a range of pro-inflammatory cytokines
and that its activation results in the recruitment and release of further
pro-inflammatory cytokines. Indeed, data from some clinical studies
demonstrate beneficial changes in disease activity in patients during
treatment with p38 MAP kinase inhibitors. For instance Smith, S. J.
(2006) Br. J. Pharmacol. 149:393-404 describes the inhibitory effect of
p38 MAP kinase inhibitors on TNFα (but not IL-8) release from human
PBMCs. Use of inhibitors of p38 MAP kinase in the treatment of chronic
obstructive pulmonary disease (COPD) is proposed. Small molecule
inhibitors targeted to p38 MAPKα/β have proved to be effective
in reducing various parameters of inflammation in cells and tissues
obtained from patients with COPD, who are generally corticosteroid
insensitive, (Smith, S. J. (2006) Br. J. Pharmacol. 149:393-404) and in
vivo animal models (Underwood, D. C. et al. Am. J. Physiol. (2000)
279:L895-902; Nath, P. et al., (2006) Eur. J. Pharmacol. 544:160-167).
Irusen and colleagues also suggested the possibility of involvement of
p38 MAPKα/β on corticosteroid insensitivity via reduction of
binding affinity of glucocorticoid receptor (GR) in nuclei (Irusen, E. et
al., (2002) J. Allergy Clin. Immunol., 109:649-657). Clinical experience
with a range of p38 MAP kinase inhibitors, including AMG548, BIRB 796,
VX702, SCIO469 and SCIO323 is described in Lee et al. (2005) Current Med.
Chem. 12:2979-2994.

[0006] COPD is a condition in which the underlying inflammation is
reported to be substantially resistant to the anti-inflammatory effects
of inhaled corticosteroids. Consequently, a superior strategy for
treating COPD would be to develop an intervention which has both inherent
anti-inflammatory effects and the ability to increase the sensitivity of
the lung tissues of COPD patients to inhaled corticosteroids. The recent
publication of Mercado et al (2007; American Thoracic Society Abstract
A56) demonstrates that silencing p38 gamma has the potential to restore
sensitivity to corticosteroids. Thus there may be a "two pronged" benefit
to the use of a p38 MAP kinase inhibitor for the treatment of COPD and
severe asthma.

[0007] However, the major obstacle hindering the utility of p38 MAP kinase
inhibitors in the treatment of human chronic inflammatory diseases has
been the toxicity observed in patients. This has been sufficiently severe
to result in the withdrawal from clinical development of many of the
compounds progressed, including all those specially mentioned above.

[0008] There remains a need to identify and develop new compounds
therapeutically useful as p38 MAP kinase inhibitors which have improved
therapeutic potential, in particular which are more efficacious, longer
acting and/or less toxic at the relevant therapeutic dose. An objective
of the present invention is to provide compounds which inhibit p38 MAP
kinase, for example with certain sub-type specificity, which show good
anti-inflammatory potential, in particular suitable for use in therapy.

SUMMARY OF THE INVENTION

[0009] According to the invention there is provided a compound of formula
(I)

##STR00002##

wherein: [0010] J represents

[0010] ##STR00003## [0011] Ar is a naphthylene or phenyl ring either of
which may be optionally substituted by one more groups (e.g. 1, 2 or 3
groups) independently selected from C1-6 alkyl, C1-6 alkoxy,
amino, C1-4 mono alkyl amino and C2-8 di-alkyl amino; [0012] Q
is N, or CH; [0013] R1 is H, [0014] phenyl, or [0015] a saturated
or unsaturated branched or unbranched C1-10 alkylene in the form of
an acyclic or alicyclic chain wherein one or more carbons in the chain
(for example 1 to 3, such as 1, 2 or 3 carbons) are optionally replaced
by a heteroatom(s) independently selected from --O--, --N-- and S(O), and
the chain is optionally substituted by: [0016] one oxo group, and/or
[0017] one or more halogen atoms (for example 1 to 6); [0018]
R2a is H, halo, saturated or unsaturated branched or unbranched
C1-8 alkylene chain, wherein one or more carbons (for example 1 to
3, such as 1, 2 or 3 carbons) are optionally replaced by a heteroatom(s)
independently selected from --O--, --N-- and/or S(O)m and the chain
is optionally substituted by one or more halogen atoms (for example 1 to
6); [0019] R2b is H, halo, C1-6 alkoxy or C1-6 alkyl
optionally substituted by OH; [0020] L is saturated or unsaturated
branched or unbranched C1-6 alkylene chain (such as a C1-3
alkylene), wherein one or more carbons (for example 1 to 3, such as 1, 2
or 3 carbons) are optionally replaced by a heteroatom selected from --O--
and/or S, and the chain is optionally substituted by one or two oxo
groups (for example 1 or 2); [0021] X is a pyridine or pyrimidine ring
optionally substituted by C1-3 alkyl, or C1-3 haloalkyl; [0022]
R3H or C1-4 alkyl; [0023] R4 is C1-10 branched or
unbranched acyclic or alicyclic alkyl chain [0024] n is 0, 1 or 2; [0025]
M is 0, 1 or 2; or a pharmaceutically acceptable salt thereof, including
all stereoisomers, tautomers and isotopic derivatives thereof.

DETAILED DESCRIPTION OF THE INVENTION

[0026] The compounds of the invention are kinase inhibitors, possessing,
for example, potent inhibitory activity at p38 MAPK enzymes and may, show
selectivity for the p38-alpha isoform over the p38-gamma isoform. The
compounds display efficacy in established in vitro assays of
anti-inflammatory activity. For example compounds of the invention
demonstrate the ability to block LPS-induced TNFα release from
differentiated U937 cells and THP-1 cells and similarly to block the
stimulated release of IL-8 from differentiated U937 cells.

[0027] According to the invention the compounds provided herein are
especially suitable for treating inflammatory pulmonary diseases by
topical administration since they are believed to have properties that
result in long residency times in the lung, resulting in an extended
duration of therapeutic action, which is consistent with twice or even
once, daily dosing.

[0028] In addition it is believed that one or more compounds of the
invention may also possess certain antiviral activities making them
useful for preventing or ameliorating the symptoms of viral infection in
patients, for example with inflammatory lung disorders.

[0029] The properties, described above (alone or in combination),
distinguish the compounds according to the invention from other known
compounds, which do not possess these desirable features.

[0031] Alkoxy as used herein refers to straight or branched chain alkoxy,
for example methoxy, ethoxy, propoxy, butoxy. Alkoxy as employed herein
also extends to embodiments in which the oxygen atom is located within
the alkyl chain, for example --C1-3 alkylOC1-3 alkyl, such as
--CH2CH2OCH3 or --CH2OCH3. Thus in one
embodiment the alkoxy is linked through carbon to the remainder of the
molecule. In one embodiment the alkoxy is linked through oxygen to the
remainder of the molecule, for example --OC1-6 alkyl. In one
embodiment the disclosure relates to a straight chain alkoxy.

[0032] Heteroalkyl as employed herein is intended to refer to a branched
or straight chain alkyl wherein one or more, such as 1, 2 or 3 carbons
are replaced by a heteroatom, selected from N, O or S(O)r, wherein r
represents 0, 1 or 2. The heteroatom may replace a primary, secondary or
tertiary carbon, that is, for example, SH, OH or NH2 for CH3,
or NH or O or SO2 for --CH2-- or N for a --CH-- or a branched
tertiary carbon, as technically appropriate.

[0033] Haloalkyl as employed herein refers to alkyl groups having 1 to 6
halogen atoms, for example 1 to 5 halogens, including perhaloalkyl, in
particular perchloroalkyl or perfluoroalkyl, more specifically
--CCl3, --CF2CF3 or CF3.

[0036] Aryl as used herein refers to, for example C6-14 mono or
polycyclic systems having from 1 to 3 rings wherein at least one ring is
aromatic including phenyl, naphthyl, anthracenyl,
1,2,3,4-tetrahydronaphthyl and the like, such as phenyl and naphthyl.

[0038] Heterocyclyl as employed herein refers to a 5 to 6 membered
saturated or partially unsaturated non-aromatic ring comprising one or
more, for example 1, 2, 3 or 4 heteroatoms independently selected from O,
N and S optionally one or two carbons in the ring may bear an oxo
substituent. The definition of C5-6 heterocycle as employed herein
refers to a 5 to 6 membered saturated or partially unsaturated
non-aromatic carbocyclic ring comprising one or more, for example 1, 2, 3
or 4 heteroatoms independently selected from O, N and S, wherein each
heteroatom replaces a carbon atom and optionally one or two carbons may
bear an oxo substitutent. Clearly any valancies of a heteroatom not
employed in forming or retaining the ring structure may be filled by
hydrogen or a substituent, as appropriate. Thus substituents on
heterocycles may be on carbon or on a heteroatom, such as nitrogen as
appropriate. Examples of heterocycles and C5-6 heterocycles include
pyrroline, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, pyrazoline,
imidazoline, pyrazolidine, imidazolidine, oxoimidazolidine, dioxolane,
thiazolidine, isoxazolidine, pyran, dihydropyran, piperidine, piperazine,
morpholine, dioxane, thiomorpholine and oxathiane.

[0040] Oxo as used herein refers to C═O and will usually be
represented as C(O).

[0041] C3-8 cycloalkyl as employed herein is intended to refer to a
saturated or partially unsaturated non-aromatic ring containing 3 to 8
carbon atoms, where the ring contains less than 8 carbons the ring may
optionally bear one or more alkyl groups such that the number of carbon
atoms in the ring plus the number of carbons in the alkyl substituents is
not more than eight in total or 10 in the case of C3-10 cycloalkyls.

[0042] C1-10 alkyl includes C2, C3, C4, C5,
C6, C7, C8 or C9 as well as C1 and C10.

[0043] C0-8 alkyl includes C1, C2, C3, C4,
C5, C6, or C7 as well as C0 and C8.

[0044] In relation to a saturated or unsaturated, branched or unbranched
C1-10 alkyl chain (or similar language used herein), wherein at
least one carbon (for example 1, 2 or 3 carbons, suitably 1 or 2, in
particular 1) is replaced by a heteroatom selected from O, N, S(O)p,
wherein said chain is optionally, substituted by one or more groups
independently selected from oxo and halogen, it will be clear to persons
skilled in the art that the heteroatom may replace a primary, secondary
or tertiary carbon, that is CH3, --CH2-- or a --CH--, a
tertiary carbon group or --CH═, as technically appropriate.

[0049] In one embodiment of the disclosure there is provided compounds of
formula (I), wherein R1 is methyl, ethyl, propyl, iso-propyl, butyl
or tert-butyl, in particular tert-butyl.

[0050] In one embodiment R1 is --C(CH3)2CH2OH.

[0051] In one embodiment R1 is cyclopropyl, or 1-methylcyclopropyl,
cyclopentyl, cyclohexyl, or 1-methylcyclohexyl, or adamantly.

[0052] In one embodiment R1 is tetrahydropyranyl or
4-methyltetrahydro-2H-pyran-4-yl.

[0053] In one embodiment R1 is --CF3, --CF2CF3 or
--CCl3.

[0054] In one embodiment R1 is phenyl.

[0055] In one embodiment the substituent R2a is in the 2, 3, or 4
position (i.e. ortho, meta or para position), in particular the para (4-)
position relative to the attachment of the aromatic ring J to the
pyrazole system.

[0056] In one embodiment R2a is methyl, ethyl, n-propyl, iso-propyl,
n-butyl or tert-butyl, in particular methyl, for example in position 3 or
4.

[0057] In one embodiment R2a is --OH, for example in position 3 or 4.

[0058] In one embodiment R2a is halo such as chloro, for example in
position 3 or 4.

[0059] In one embodiment R2a is --C1-6 alkyl substituted by a
hydroxyl group such as --CH2OH, for example in position 3 or 4.

[0060] In one embodiment R2a is --C1-6 alkoxy, such as
--OCH3, for example in position 3 or 4.

[0061] In one embodiment R2a is --SC1-6 alkyl, such as
--SCH3, for example in position 3 or 4.

[0062] In one embodiment R2a is --SO2C1-6 alkyl, such as
--SO2CH3 for example in the 3 or 4 position.

[0063] In one embodiment R2a is --OCF3, for example located in
position 3 or 4.

[0064] In one embodiment R2a is --NR''R'' wherein R'' is H,
--C1-3 alkyl or --SO2C1-3alkyl, and R'' is H or
--C1-3 alkyl, for example located in position 3 or 4. In one
embodiment R2a is --NH2, for example in position 3 or 4.

[0065] In one embodiment R2a is --NHSO2CH3, for example in
position 3 or 4.

[0066] In one embodiment R2b is H.

[0067] In one embodiment R2b is halo such as chloro, for example in
position 3.

[0068] In one embodiment R2a is chloro and R2b is chloro, for
example 3,4-dichloro.

[0069] In one embodiment R2a chloro is and R2b is --OCH3,
for example in positions 3,4 respectively.

[0070] In one embodiment R2a is --OCH3 and R2b is
--OCH3, for example in position 3,4.

[0071] In one embodiment R2a chloro is and R2b is --OH, for
example in position 3,4 respectively.

[0072] In one embodiment the substituent R2a is in the 2, 3, or 4
position (i.e. ortho, meta or para position), in particular the para (4-)
position relative to the attachment of the aromatic ring J to the
pyrazole system.

[0073] In one embodiment R2a is methyl, ethyl, n-propyl, iso-propyl,
n-butyl or tert-butyl, in particular methyl, for example in position 3 or
4.

[0074] In one embodiment R2a is --OH, for example in position 3 or 4.

[0075] In one embodiment R2a is halo such as chloro, for example in
position 3 or 4.

[0076] In one embodiment R2a is --C1-6 alkyl substituted by a
hydroxyl group such as --CH2OH, for example in position 3 or 4.

[0077] In one embodiment R2a is --C1-6 alkoxy, such as
--OCH3, for example in position 3 or 4.

[0078] In one embodiment R2a is --SC1-6 alkyl, such as
--SCH3, for example in position 3 or 4.

[0079] In one embodiment R2a is --SO2C1-6 alkyl, such as
--SO2CH3 for example in the 3 or 4 position.

[0080] In one embodiment R2a is --OCF3, for example located in
position 3 or 4.

[0081] In one embodiment R2a is --NR''R'' wherein R'' is H,
--C1-3 alkyl or --SO2C1-3alkyl, and R'' is H or
--C1-3 alkyl, for example located in position 3 or 4. In one
embodiment R2a is --NH2, for example in position 3 or 4.

[0082] In one embodiment R2a is --NHSO2CH3, for example in
position 3 or 4.

[0083] In one embodiment R2b is H.

[0084] In one embodiment R2b is halo such as chloro, for example in
position 3.

[0085] In one embodiment R2a is chloro and R2b is chloro, for
example 3,4-dichloro.

[0086] In one embodiment R2a chloro is and R2b is --OCH3,
for example in positions 3,4 respectively.

[0087] In one embodiment R2a is --OCH3 and R2b is
--OCH3, for example in position 3,4.

[0088] In one embodiment R2a chloro is and R2b is --OH, for
example in position 3,4 respectively.

[0089] In embodiments of the invention wherein the group Q represents N,
the substituents R2a and R2b on the ring are pharmaceutically
acceptable and do not include those of a highly reactive nature (such as
a halogen atom disposed ortho to the heteroatom) such that compounds of
formula (I) would thereby be rendered unstable and consequently
unsuitable for their intended utility.

[0090] In one embodiment J is pyridine and R2a is methyl, ethyl,
n-propyl, iso-propyl, n-butyl or tert-butyl, in particular methyl, for
example in position 2 or 3.

[0091] In one embodiment J is pyridine and R2a is --C1-6 alkyl
substituted by a hydroxyl group such as --CH2OH, for example in
position 2 or 3.

[0092] In one embodiment J is pyridine and R2a is --C1-6 alkoxy,
such as --OCH3, for example in position 2 or 3.

[0093] In one embodiment J is pyridine and R2a is --SC1-6 alkyl,
such as --SCH3, for example in position 2 or 3.

[0094] In one embodiment J is pyridine and R2a is --SO2C1-6
alkyl, such as --SO2CH3 for example in the 3 position.

[0095] In one embodiment J is pyridine and R2a is --OCF3, for
example located in position 3.

[0096] In one embodiment when J is pyridine and R2a is --NR''R''
wherein R'' is H, --C1-3 alkyl or --SO2C1-3alkyl, and R''
is H or --C1-3 alkyl, for example located in position 2 or 3. In one
embodiment R2a is --NH2, for example in position 2 or 3.

[0097] In one embodiment J is pyridine and R2a is
--NHSO2CH3, for example in position 2 or 3.

[0098] In one embodiment J is pyridine and R2b is H.

[0099] In one embodiment L represents O, CH2, C═O or S(O)t
where t is 0, 1 or 2, in particular 0 or 2.

[0100] In one embodiment L represents --OCH2-- or
--OCH2CH2--.

[0101] In one embodiment X is pyridine.

[0102] In one embodiment R3 is H.

[0103] In one embodiment R4 is an unbranched alkyl, for example
methyl, ethyl, propyl, butyl, pentyl, hexyl, nonyl, decyl, such as
methyl.

[0104] In one embodiment R4 is a branched alkyl, for example
--CH2CH(CH3)2, --C(CH3)3,
CH2CH(CH3)CH2CH3 and the like.

[0105] In one embodiment the disclosure relates to compounds of formula
(IA):

[0118] In one embodiment of the invention the compounds of formula (IF)
comprise of structures in which the substituent --NR3C(O)R4 is
located at position 2 of the pyridine ring.

[0119] In one embodiment the compound is: [0120]
N-(4-(2-(4-(3-(3-tert-Butyl-1-p-tolyl-1H-pyrazol-5-yl)ureido)naphthalen-1-
-yloxy)ethyl)pyridin-2-yl)acetamide; [0121]
N-(4-(((4-(3-(3-(tert-Butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)ureido)naphthale-
n-1-yl) oxy)methyl)pyridin-2-yl)acetamide; [0122]
N-(4-((4-(3-(3-(tert-Butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)ureido)naphthalen-
-1-yl) oxy)pyridin-2-yl)acetamide; or a pharmaceutically acceptable salt
of any one thereof, including all stereoisomers, tautomers and isotopic
derivatives thereof.

[0123] Examples of salts of compound (I) include all pharmaceutically
acceptable salts, such as, without limitation, acid addition salts of
mineral acids such as HCl and HBr salts and addition salts of organic
acids such as a methanesulfonic acid salt. Further example salts include
pharmaceutically acceptable acid addition salts which can conveniently be
obtained by treating the base form with an appropriate acid, for example,
inorganic acids such as sulfuric, nitric and phosphoric acids; or organic
acids such as, for example, acetic, propanoic, hydroxyacetic, lactic,
pyruvic, oxalic (i.e. ethanedioic), malonic, succinic butanedioic acid),
maleic, fumaric, malic, tartaric, citric, ethanesulfonic,
benzenesulfonic, p-toluenesulfonic, cyclamic, salicylic, p-aminosalicylic
or pamoic acids.

[0124] The disclosure herein extends to solvates of compounds of formula
(I). Examples of solvates include hydrates.

[0125] The compounds of the disclosure include those where the atom
specified is a naturally occurring or non-naturally occurring isotope. In
one embodiment the isotope is a stable isotope. Thus the compounds of the
disclosure include, for example, deuterium containing compounds and the
like.

[0126] The compounds described herein may include one or more stereogenic
centres, and the disclosure extends to include racemates, and to both
enantiomers (for example each substantially free of the other enantiomer)
and all stereoisomers, such as diastereomers resulting therefrom. In one
embodiment one enantiomeric form is present in a purified form that is
substantially free of the corresponding entaniomeric form.

[0127] The disclosure also extends to all polymorphic forms of the
compounds herein defined.

[0128] Compounds of formula (I) can be prepared by a process comprising
reacting a compound of formula (II):

##STR00012##

wherein J, L X, R1, R3 and Q are as defined above for compounds
of formula (I) with a compound of formula (III):

##STR00013##

Where R4 is as defined above and LG1 is a leaving group for
example halogen, such as chloro. The reaction is suitably carried out in
the presence of an organic base such as DIPEA or triethylamine and in an
aprotic solvent or solvent mixture such as a mixture of DCM and DMF.

[0129] Alternatively compounds of formula (I) can be prepared by reacting
a compound of formula (V):

##STR00014##

where R1 and J are as defined above for compounds of formula (I),
with a compound of formula (IV):

##STR00015##

wherein LG3 and LG4 each independently represent leaving
groups, to generate a compound of formula (VIa), for example when
LG3 and LG4 both represent imidazolyl; or a compound of formula
(VIb), for example when the groups LG3 and LG4 represent
halogen, such chloro or trihalomethoxy such as trichloromethoxy)

##STR00016##

followed by reaction with a compound of formula (VII):

##STR00017##

wherein R3, R4, L, X, and Ar are as defined above for compounds
of formula (I). The reaction is suitably carried out in an aprotic
solvent such as dichloromethane in the presence of a sterically hindered
base, for example DIPEA.

[0130] It will be understood by persons skilled in the art that compounds
represented by formulae (VIa) and (VIb) are generally reactive
intermediates, and may be formed in situ and reacted directly, without
isolation, with a compound of formula (VII) to provide a compound of
formula (I). Furthermore it will be understood by those skilled in the
art that the use of appropriate protective groups may be required during
the processes described above, for any of the groups R1, R2a
and R2b on J that comprise chemically sensitive functional groups,
for example that contain a OH group or an NH2 function

[0131] Compounds of formula (II) can be prepared by reacting a compound of
formula (VIII) wherein R3, Ar, L and X are as defined above for
compounds of formula (I)

H2N--Ar-L-X--NHR3 (VIII)

with a compound of formula (VIa) or a compound of formula (VIb),
generated as described above from a compound of formula (V), in an
aprotic solvent such as dichloromethane and a suitable base, for example
DIPEA, employing, where necessary, appropriate protective groups for
chemically sensitive functionality.

[0132] Compounds of formula (VII) may be prepared by reacting a compound
of formula (IX):

O2N--Ar-L-X--NHR3 (IX)

wherein R3, Ar, L and X are as defined above for compounds of
formula (I), with a compound of formula (III). The reaction is suitably
carried out in the presence of an organic base such as DIPEA or
triethylamine in an aprotic solvent or solvent mixture, such as DCM and
DMF.

[0133] From the intermediate so generated compounds of formula (VII) are
then revealed by reduction of the nitro arene to the corresponding amine,
for example by hydrogenation in the presence of a suitable catalyst, such
as palladium on carbon. In certain cases it may be advantageous to
conduct the reduction step chemically, for example under dissolving metal
conditions, such as with iron in glacial acetic acid.

[0134] Compounds of formula (V) can be derived from the condensation of a
phenylhydrazine of formula (X) or (Xa):

##STR00018##

wherein J, R2a, R2b and Q are as are defined above for
compounds of formula (I), with a compound of formula (XI):

##STR00019##

wherein R1 is as defined above for compounds of formula (I).

[0135] The reaction may be effected in an alcoholic solvent such as
ethanol and in the presence of a mineral acid, such as HCl followed by
treatment with a base, such as lithium hydroxide, in a solvent such as
THF, to liberate the product as a free base.

[0136] Compounds of formula (I) wherein any of the substituents R1 or
R2a or R2b contains a sensitive functional group may be
prepared from a compound of formula (V), by the processes described
above, in which the said functionality is suitably protected during the
synthetic transformations, followed by an appropriate deprotection step.
For example a compound of formula (V) in which R1, or R2a or
R2b comprises a hydroxyalkyl, may be converted into a compound of
formula (I) by the methods described above, by protecting the hydroxyl
functionality, for example as a silyl ether. The hydroxyl group can be
revealed at the end of the synthetic sequence by cleavage of the
protective group: for example a silyl protective group may be removed
with, for example, tetrabutylammonium fluoride.

[0137] Compounds of formula (V) wherein any of the substituents R1,
or R2a or R2b consists of a hydroxyalkyl such as, for example,
--(CH2)xCH2OH may be prepared by the reduction of
compounds of formula (V) in which one or more of the substituents
R1, or R2a or R2b comprises of the corresponding acid such
as, for example --(CH2)xCO2H, wherein x is as appropriate
for compounds of formula (I), employing a reagent such as borane in a
suitable solvent, for example THF. The hydroxyl may then be optionally
protected, for example as a silyl ether, and this intermediate converted
into a compound of formula (I) in which R1, or R2a or R2b
is a protected hydroxyalkyl group, by one of the methods described above.

[0138] Compounds of formula (VIII) may be prepared by the reduction of a
compound of formula (IX) to the corresponding amine, for example using
hydrogenation in the presence of a suitable catalyst such as palladium on
carbon.

[0139] Certain compounds of formula (IX) wherein the group L comprises of
a fragment represented by --O(CH2)1-5-- may be obtained by the
reaction of a compound of formula (XIIa), wherein X and R3 are as
defined for compounds of formula (I)

HO--(CH2)1-5--X--NHR3 XIIa)

and a compound of formula (XIII):

O2N--Ar--OH (XIII)

wherein Ar is as defined above for compounds of formula (I), for example
under Mitsunobu coupling conditions, typically in the presence of a
triarylphosphine such as triphenylphosphine and a dialkyl
azodicarboxylate such as diisopropylazodicarboxylate. The reaction is
suitably carried out in a polar aprotic solvent such as THF.

[0140] Alternatively, certain compounds of formula (IX) wherein the group
L comprises of a fragment represented by --O(CH2)1-5-- may be
obtained by a nucleophilic aromatic substitution (SNAr) reaction of
a compound of formula (XIIa) with a compound of (XIV)

O2N--Ar--Z (XIV)

wherein Ar is as defined above for compounds of formula (I) and Z is a
halogen atom, most preferably fluorine. The reaction is conveniently
conducted in the presence of a strong base such as sodium hydride and in
an aprotic solvent such as THF.

[0141] Certain compounds of formula (IX) wherein the group L is O, that is
an oxa linker, may be obtained by the reaction of a compound of formula
(XIIb), wherein X and R3 are as defined for compounds of formula (I)

HO--X--NHR3 (XIIb)

and a compound of formula (XIV). The reaction may be conducted in the
presence of an organic base such DBU in a polar aprotic solvent such as
acetonitrile.

[0142] Certain compounds of formula (IX) wherein the group L is O, that is
an oxa linker, may be obtained by the reaction of a compound of formula
(XIIc), wherein X and R3 are as defined for compounds of formula (I)
and Y is a halogen atom preferably chlorine

Y--X--NHR3 (XIIc)

and a compound of formula (XIII). The reaction may be effected in a polar
aprotic solvent, such as NMP, in the presence of a strong mineral acid,
such conc. hydrochloric acid and at an elevated temperature for example
at 170° C. to 190° C.

[0143] Certain compounds of formula (VII) wherein the group L is O, that
is an oxa linker, may be obtained via the reaction of a compound of
formula (XIId),

##STR00020##

wherein X, R3 and R4 are as defined for compounds of formula
(I) with a compound of formula (XIV) providing compounds of formula (XV).

##STR00021##

[0144] Compounds of formula (VII) are revealed from compounds of formula
(XV) by the reduction of the nitroarene to the corresponding amine. This
transformation may be conducted by catalytic hydrogenation in a suitable
solvent mixture such as a mixture of DCM, MeOH and acetic acid, over an
appropriate metal catalyst, for example platinum supported on graphite,
at RT. Alternatively it may be advantageous to conduct the reduction step
by chemical means, for example using a metal such as iron powder, in an
acid, such as glacial acetic acid at an elevated temperature, such as
60° C.

[0145] Certain compounds of formula (I) wherein Ar, X, R1, and
R3 are as previously defined above and the group L is S, that is a
thio ether linker; may be prepared from a compound of formula (IIb), by
the processes described above for a compound of formula (II) A compound
of formula (IIb) may be obtained from a compound of (VIII) wherein Ar,
R3 and X are as defined above and L is S; by reaction with a
compound of formula (VIa) or a compound of formula (VIb) as described
above.

##STR00022##

[0146] Compounds of formula (VIII) wherein R3, Ar, J and X are as
defined above and L is S, that is L is a thioether linker, may be
prepared from a compound of formula (VIIIc) wherein the group Ar1 is
a leaving group with an electron rich aromatic nucleus, thereby making
the radical --CH2Ar1 susceptible to cleavage by acidolysis. A
suitable aromatic group for this purpose is, for example
2,4-dimethoxybenzene and the like. The desired compound of formula
(VIII), as defined above, may be obtained from the compound of formula
(VIIIc) by acid mediated cleavage, for example with hydrochloric acid in
an alcoholic solvent such methanol, at an elevated temperature such as at
reflux:

##STR00023##

[0147] Compounds of formula (VIIIc) are obtainable from the reaction of a
compound of formula (XVI) wherein Ar and X are as defined above and Y is
a halogen atom, preferably chlorine, with a compound of formula (XVII),
wherein R3 and Ar1 are as defined above. The reaction may be
carried out by heating the compound of formula (XVII) as a solution in
the neat amine of formula (XVII) at a suitable temperature, such as
120° C.:

##STR00024##

wherein X, Y, Ar1 and R3 are defined above.

[0148] Compounds of formula (XVI) may be prepared by reduction of
compounds of formula (XVIII), for example by catalytic reduction using
hydrogen and a suitable metal catalyst. The reduction step is
conveniently carried out in a mixture of solvents such as EtOAc, MeOH and
AcOH, over platinum on carbon, at an elevated temperature such as
50° C.

O2N--Ar--S--X--Y (XVIII)

[0149] Compounds of formula (XVIII) may be prepared by the reaction of
compounds of formula (XIV), as defined above, with a compound of formula
(XIX)

Z--X--Y (XIX)

[0150] wherein X is as defined above, Z is a halogen atom, preferably
fluorine and Y is a halogen atom, preferably chlorine together with a
suitable sulfur nucleophile. For example the reaction can be carried
using sodium hydrogensulfide as the sulfur source in a polar aprotic
solvent such as DMF and in the presence of a organic base, for example
DIPEA, at ambient temperature.

[0151] Certain compounds of formula (I) wherein, R1, R2a,
R2b, Ar and X are as previously defined, R3 is H and L is
SO2, that is L is a sulfonyl linker, may be prepared from a compound
of formula (IIc) by one or more of the processes described above.

##STR00025##

[0152] Compounds of formula (IIc) can be derived from a compound of
formula (XX),

H2N--Ar--SO2--X--NHP1 (XX)

OCN--Ar--SO2--X--NHP1 (XXI)

wherein Ar, X and P1 are as previously defined, by conversion, in
situ, into an isocyanate of formula (XXI) followed by, without isolation,
reaction with a compound of formula (V). The transformation may be
effected by exposing the compound of formula (XX) to a compound of
formula (IVb); wherein, for example, the group LG3 is halogen such
as chlorine and the group LG4 is trihalomethoxy such as
trichloromethoxy, such that the compound of formula (IVb) is diphosgene,
and subsequently of admixing the compound of formula (V). The reaction is
conveniently conducted in an inert aprotic solvent such as DCM and may be
cooled, for example to 0° C. The desired compounds of formula
(IIc) are then revealed from the products so obtained by a deprotection
step. For example, where P1 represents a Boc group the compounds of
formula (IIc) are obtained following removal of the protective group with
an acid such as TFA, in an inert solvent such as DCM, conveniently at
0° C. to RT.

[0153] Compounds of formula (XX), wherein Ar, X and P1 are as
previously defined, may be obtained by the reduction of compounds of
formula (XXII).

O2N--Ar--SO2--X--NHP1 (XXII)

The reduction may be carried out, for example, by hydrogenation over a
suitable catalyst, such as palladium on carbon, in an appropriate solvent
system such as a mixture of EtOAc, MeOH and AcOH, and if necessary with
warming, for example at 30° C.

[0154] Compounds of formula (XXII) are accessible from compounds of
formula (XVIIIa)

##STR00026##

wherein Ar and X are as previously defined above and Y is a halogen atom,
preferably chlorine, by an amidation reaction employing a compound of
formula (XXIII). A suitable compound of formula (XXIII) for this
transformation is that in which R represents tert-butyl such that the
said compound (XXIII) is H2NC(O)OtBu. Suitable conditions for
this conversion are, for example, the reaction of a compound of formula
(XVIIIa) with a compound of formula (XXV) in the presence of a catalytic
system, such as that generated from Pd2(dba)3 in the presence
of the phosphine ligand such as XantPhos. The reaction is conveniently
conducted in a polar aprotic solvent such as THF and in the presence of a
base, for example, an inorganic base such as cesium carbonate.

[0155] Compounds of formula (XVIIIa) wherein Ar is as previously defined
and X is pyridine may be derived from a compound of formula (XXIV):

##STR00027##

by oxidation to a compound of formula (XXV) followed by treatment with a
chlorinating agent. A suitable oxidising reagent for the conversion of a
compound of formula (XXIV) into a compound of formula (XXV) is, for
example, m-CPBA. The reaction may be effected in a halogenated solvent
such as DCM and typically below RT, for example at 0° C. The
subsequent chlorination step may be carried out using a reagent such as
phosphorus oxychloride at an elevated temperature, for example at
100° C.

[0156] Compounds of formula (XXIV) may be obtained from the reaction of a
compound of formula (XIV) as defined previously, with a compound of
formula (XXVI):

##STR00028##

The reaction is conveniently conducted in a polar aprotic solvent such as
DMF and typically in the presence of a base, for example an inorganic
base such as potassium carbonate, and if necessary with cooling, for
example, to 0° C.

[0157] Compounds of formulae (III), (IVa), (IVb), (V), (X), (XI), (XIIa),
(XIIb), (XIIc), (XIII), (XIV), (XVII), (XIX), (XXIII), (XXVI) and certain
other compounds illustrated in the schemes are either commercially
available, or were obtained using the cited procedures, or can be readily
prepared by conventional methods by those skilled in the art. See for
example Regan, J. et al.; J. Med. Chem., 2003, 46, 4676-4686,
WO00/043384, WO2007/087448 and WO2007/089512.

[0158] Protecting groups may be required to protect chemically sensitive
groups during one or more of the reactions described above, to ensure
that the process is efficient. Thus if desired or necessary, intermediate
compounds may be protected by the use of conventional protecting groups.
Protecting groups and means for their removal are described in
"Protective Groups in Organic Synthesis", by Theodora W. Greene and Peter
G. M. Wuts, published by John Wiley & Sons Inc; 4th Rev Ed., 2006,
ISBN-10: 0471697540.

[0159] Novel intermediates are claimed as an aspect of the invention.

[0160] In one aspect the compounds are useful in treatment, for example
COPD and/or asthma.

[0161] The p38MAPK inhibitory compounds developed to date have typically
been intended for oral administration. This method of dosing involves
optimization to achieve an adequate duration of action by selecting
compounds that have an appropriate pharmacokinetic profile. This strategy
ensures that a therapeutically effective drug concentration is
established and maintained after and between doses to provide the desired
clinical benefit. The inevitable consequence of this regimen is that all
body tissues, especially liver and gut, are likely to be exposed
chronically to therapeutically active concentrations of the drug, whether
or not they are adversely affected in the diseased state.

[0162] An alternative strategy is to design treatment approaches in which
the drug is dosed directly to the inflamed organ (topical therapy). While
this approach is not suitable for treating all chronic inflammatory
diseases, it has been extensively exploited in lung diseases (asthma,
COPD), skin diseases (atopic dermatitis and psoriasis), nasal diseases
(allergic rhinitis) and gastrointestinal diseases (ulcerative colitis).

[0163] In topical therapy, efficacy can be achieved either by ensuring
that the drug has a sustained duration of action and is retained in the
relevant organ to minimize the risk of systemic toxicity; or by producing
a formulation which generates a "reservoir" of the active drug which is
available to sustain the drug's desired effects. The first approach is
exemplified by the anticholinergic drug tiotropium (Spiriva). This
compound is administered topically to the lung as a treatment for COPD,
and has an exceptionally high affinity for its target receptor resulting
in a very slow off rate and a consequent sustained duration of action.

[0164] There is provided according to one aspect of the present disclosure
use of a compound of formulation as a p38 MAP kinase inhibitor, for
example administered topically to the lung.

[0165] In one aspect of the disclosure the compounds herein are
particularly suitable for topical delivery, such as topical delivery to
the lungs, in particular for the treatment of COPD.

[0166] Thus is one aspect there is provided use of compounds of formula
(I) for the treatment of COPD and/or asthma, in particular COPD or severe
asthma, by inhalation i.e. topical administration to the lung.
Advantageously, administration to the lung allows the beneficial effects
of the compounds to be realised whilst minimising the side-effects for
patients.

[0167] In one aspect the compounds have a longer duration of actions than
BIRB 796.

[0168] In one embodiment the compounds are suitable for sensitizing
patients to treatment with a corticosteroid.

[0169] The compounds herein may also be useful for the treatment of
rheumatoid arthritis.

[0170] Further, the present invention provides a pharmaceutical
composition comprising a compound according to the disclosure optionally
in combination with one or more pharmaceutically acceptable diluents or
carriers.

[0171] Diluents and carriers may include those suitable for parenteral,
oral, topical, mucosal and rectal administration.

[0172] As mentioned above, such compositions may be prepared e.g. for
parenteral, subcutaneous, intramuscular, intravenous, intra-articular or
peri-articular administration, particularly in the form of liquid
solutions or suspensions; for oral administration, particularly in the
form of tablets or capsules; for topical e.g. pulmonary or intranasal
administration, particularly in the form of powders, nasal drops or
aerosols and transdermal administration; for mucosal administration e.g.
to buccal, sublingual or vaginal mucosa, and for rectal administration
e.g. in the form of a suppository.

[0173] The compositions may conveniently be administered in unit dosage
form and may be prepared by any of the methods well-known in the
pharmaceutical art, for example as described in Remington's
Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa.,
(1985). Formulations for parenteral administration may contain as
excipients sterile water or saline, alkylene glycols such as propylene
glycol, polyalkylene glycols such as polyethylene glycol, oils of
vegetable origin, hydrogenated naphthalenes and the like. Formulations
for nasal administration may be solid and may contain excipients, for
example, lactose or dextran, or may be aqueous or oily solutions for use
in the form of nasal drops or metered spray. For buccal administration
typical excipients include sugars, calcium stearate, magnesium stearate,
pregelatinated starch, and the like.

[0174] Compositions suitable for oral administration may comprise one or
more physiologically compatible carriers and/or excipients and may be in
solid or liquid form. Tablets and capsules may be prepared with binding
agents, for example, syrup, acacia, gelatin, sorbitol, tragacanth, or
poly-vinylpyrollidone; fillers, such as lactose, sucrose, corn starch,
calcium phosphate, sorbitol, or glycine; lubricants, such as magnesium
stearate, talc, polyethylene glycol, or silica; and surfactants, such as
sodium lauryl sulfate. Liquid compositions may contain conventional
additives such as suspending agents, for example sorbitol syrup, methyl
cellulose, sugar syrup, gelatin, carboxymethyl-cellulose, or edible fats;
emulsifying agents such as lecithin, or acacia; vegetable oils such as
almond oil, coconut oil, cod liver oil, or peanut oil; preservatives such
as butylated hydroxyanisole (BHA) and butylated hydroxytoluene (BHT).
Liquid compositions may be encapsulated in, for example, gelatin to
provide a unit dosage form.

[0176] A dry shell formulation typically comprises of about 40% to 60%
concentration of gelatin, about a 20% to 30% concentration of plasticizer
(such as glycerin, sorbitol or propylene glycol) and about a 30% to 40%
concentration of water. Other materials such as preservatives, dyes,
opacifiers and flavours also may be present. The liquid fill material
comprises a solid drug that has been dissolved, solubilized or dispersed
(with suspending agents such as beeswax, hydrogenated castor oil or
polyethylene glycol 4000) or a liquid drug in vehicles or combinations of
vehicles such as mineral oil, vegetable oils, triglycerides, glycols,
polyols and surface-active agents.

[0177] Suitably the compound of formula (I) is administered topically to
the lung. Hence we provide according to the invention a pharmaceutical
composition comprising a compound of the disclosure optionally in
combination with one or more topically acceptable diluents or carriers.
Topical administration to the lung may be achieved by use of an aerosol
formulation. Aerosol formulations typically comprise the active
ingredient suspended or dissolved in a suitable aerosol propellant, such
as a chlorofluorocarbon (CFC) or a hydrofluorocarbon (HFC). Suitable CFC
propellants include trichloromonofluoromethane (propellant 11),
dichlorotetrafluoromethane (propellant 114), and dichlorodifluoromethane
(propellant 12). Suitable HFC propellants include tetrafluoroethane
(HFC-134a) and heptafluoropropane (HFC-227). The propellant typically
comprises 40% to 99.5% e.g. 40% to 90% by weight of the total inhalation
composition. The formulation may comprise excipients including
co-solvents (e.g. ethanol) and surfactants (e.g. lecithin, sorbitan
trioleate and the like). Aerosol formulations are packaged in canisters
and a suitable dose is delivered by means of a metering valve (e.g. as
supplied by Bespak, Valois or 3M).

[0178] Topical administration to the lung may also be achieved by use of a
non-pressurised formulation such as an aqueous solution or suspension.
This may be administered by means of a nebuliser. Topical administration
to the lung may also be achieved by use of a dry-powder formulation. A
dry powder formulation will contain the compound of the disclosure in
finely divided form, typically with a mass mean diameter (MMAD) of 1-10
microns. The formulation will typically contain a topically acceptable
diluent such as lactose, usually of large particle size e.g. a mass mean
diameter (MMAD) of 100 μm or more. Example dry powder delivery systems
include SPINHALER, DISKHALER, TURBOHALER, DISKUS and CLICKHALER.

[0179] Compounds according to the disclosure are intended to have
therapeutic activity. In a further aspect, the present invention provides
a compound of the disclosure for use as a medicament.

[0181] Compounds of the disclosure may also re-sensitise the patient's
condition to treatment with a corticosteroid, when the patient's
condition has become refractory to the same.

[0182] Compounds according to the disclosure are also expected to be
useful in the treatment of certain conditions which may be treated by
topical or local therapy including allergic conjunctivitis,
conjunctivitis, allergic dermatitis, contact dermatitis, psoriasis,
ulcerative colitis, inflamed joints secondary to rheumatoid arthritis or
osteoarthritis.

[0183] Compounds of the disclosure are also expected to be useful in the
treatment of certain other conditions including rheumatoid arthritis,
pancreatitis, cachexia, inhibition of the growth and metastasis of
tumours including non-small cell lung carcinoma, breast carcinoma,
gastric carcinoma, colorectal carcinomas and malignant melanoma.

[0184] Compounds of the disclosure are believed to be useful as anti-viral
agents, for example in the treatment of conditions including influenza.
In particular the compounds of the present disclosure may be suitable for
the use in the treatment or prevention of said viral infection and in
particular may be capable of reducing viral load and/or ameliorating
symptoms after infection.

[0185] Thus, in a further aspect, the present invention provides a
compound as described herein for use in the treatment of the above
mentioned conditions.

[0186] In a further aspect, the present invention provides use of a
compound as described herein for the manufacture of a medicament for the
treatment of the above mentioned conditions.

[0187] In a further aspect, the present invention provides a method of
treatment of the above mentioned conditions which comprises administering
to a subject an effective amount of a compound of the disclosure or a
pharmaceutical composition thereof.

[0188] The word "treatment" is intended to embrace prophylaxis as well as
therapeutic treatment.

[0189] A compound of the disclosure may also be administered in
combination with one or more other active ingredients e.g. active
ingredients suitable for treating the above mentioned conditions. For
example possible combinations for treatment of respiratory disorders
include combinations with steroids (e.g. budesonide, beclomethasone
dipropionate, fluticasone propionate, mometasone furoate, fluticasone
furoate), beta agonists (e.g. terbutaline, salbutamol, salmeterol,
formoterol) and/or xanthines (e.g. theophylline).

EXPERIMENTAL SECTION

Abbreviations

[0190] Abbreviations used herein are as defined in the table below. Any
abbreviations not defined are intended to convey their generally accepted
meaning.

[0192] All starting materials and solvents were either obtained from
commercial sources or prepared according to the literature citation.
Unless otherwise stated all reactions were stirred. Organic solutions
were routinely dried over anhydrous magnesium sulfate. Hydrogenations
were preformed on a Thales H-cube flow reactor under the conditions
stated.

[0193] Column chromatography was performed on pre-packed silica (230-400
mesh, 40-63 μM) cartridges using the amount indicated. SCX was
purchased from Supelco and treated with 1M hydrochloric acid prior to
use. Unless stated otherwise the reaction mixture to be purified was
first diluted with MeOH and made acidic with a few drops of AcOH. This
solution was loaded directly onto the SCX and washed with MeOH. The
desired material was then eluted by washing with 1% NH3 in MeOH.

[0204] The aminopyrazole Intermediate A1 was prepared by the condensation
of p-tolylhydrazine hydrochloride and 4,4-dimethyl-3-oxopentanenitrile
according to the published procedure: Cirillo, P. F. et al., WO
2000/43384, 27 Jul. 2000.

[0206] To a solution of ethyl
2-(2-(tert-butoxycarbonylamino)pyridin-4-yl)acetate (WO 2007089512) (10.0
g, 35.7 mmol) under N2 in THF (100 mL), at -78° C., was added
a solution of DIBAL in THF (1.0M, 71.0 mL, 71.0 mmol) over 1 hr. The
reaction mixture was stirred at -78 to -60° C. for 40 min and was
then warmed to -15° C. over 1 hr. The solution was re-cooled to
-78° C. and was treated with a further aliquot of DIBAL solution
(36.0 mL, 36.0 mmol) and was allowed to warm to -40° C. and
stirred for 1 hr. The reaction was quenched by the cautious addition of
water (10 mL), followed MgSO4. The solids were removed by filtration
and the filtrate was evaporated in vacuo. The residue was purified by
flash column chromatography (SiO2, 330 g, EtOAc in hexanes, 65% v/v,
isocratic elution) to give tert-butyl
4-(2-hydroxyethyl)pyridin-2-ylcarbamate, (6.0 g, 64%) as a yellow solid:
m/z 239 (M+H)+(ES+).

[0207] To a solution of tert-butyl 4-(2-hydroxyethyl)pyridin-2-ylcarbamate
(6.0 g, 25 mmol) in THF (70 mL) at 0° C. was added sodium hydride
(2.52 g, 60% wt dispersion in mineral oil, 63.0 mmol) and the bright
yellow suspension stirred for 20 min and then treated with
1-fluoro-4-nitronaphthalene (4.81 g, 25.2 mmol) in a single portion.
After stirring at RT for 2 hr the mixture was treated with water (100 mL)
followed by EtOAc (100 mL) and the solid which formed at the interface
was collected by filtration. The organic phase was separated and was
washed with saturated aq. NaHCO3 and brine and was then dried and
evaporated in vacuo to furnish an orange solid. The two solids were
combined and triturated with MeOH (50 mL) to provide tert-butyl
4-(2-(4-nitronaphthalen-1-yloxy)ethyl)pyridin-2-ylcarbamate, as a yellow
solid (11.0 g, 98%): m/z 410 (M+H)+(ES+).

[0208] To a suspension of tert-butyl
4-(2-(4-nitronaphthalen-1-yloxy)ethyl)pyridin-2-ylcarbamate (900 mg, 2.20
mmol) in DCM (10.0 mL) was added TFA (10.0 mL) and the reaction mixture
was stirred at RT overnight. The resulting mixture was evaporated in
vacuo and the residue subjected to SCX capture and release. The crude
product so obtained was taken up into THF (8.0 mL) and DIPEA (660 μl,
3.8 mmol) and then acetyl chloride (147 μl, 2.06 mmol) were added.
After stirring for 1 hr, the mixture was diluted with saturated aq.
NaHCO3 (10.0 mL) and was extracted with EtOAc (2×20 mL). The
combined organic layers were washed with brine and then dried, and
evaporated in vacuo. The residue was taken up in a mixture of
acetonitrile and a solution of NH3 in MeOH (7M, 1:1 v/v, 20 mL) and
after 10 min was re-evaporated in vacuo. The residue was triturated with
MeOH (10.0 mL) to afford
N-(4-(2-(4-nitronaphthalen-1-yloxy)ethyl)pyridin-2-yl)acetamide, as a
yellow solid (570 mg, 74%): m/z 352 (M+H)+(ES+).

[0209] A solution of
N-(4-(2-(4-nitronaphthalen-1-yloxy)ethyl)pyridin-2-yl)acetamide (570 mg,
1.62 mmol) in a mixture of AcOH: MeOH (6:1 v/v, 54 mL) was subjected to
hydrogenation by passage through a Thales H-cube (1 mLmin-1, 30 mm,
10% Pt/C Cat-Cart, full H2, 45° C.). The solvent was removed
by evaporation in vacuo, and, the residue was subjected to SCX capture
and release to furnish the title compound, Intermediate B, (550 mg,
100%): m/z 322 (M+H)+(ES+).

[0211] To a solution of 4-nitronaphthol (5.17 g, 27.3 mmol),
triphenylphosphine (10.75 g, 41.0 mmol) and 2-aminopyridine-4-methanol
(5.09 g, 41.0 mmol) in THF (50 mL) at -15° C. was added dropwise
DIAD (8.07 mL, 41.0 mmol) and the mixture then allowed to warm to RT and
stirred overnight. The volatiles were removed in vacuo and the residue
was triturated with EtOAc (150 mL), and the crude product was collected
by filtration and washed with EtOAc (100 mL). A second trituration with
MeOH (100 mL) gave 2-amino-4-((4-nitronaphthalen-1-yloxy)methyl)pyridine
(4.54 g, 56%) as a yellow solid: m/z 296 (M+H)+(ES+).

[0212] A solution of 2-amino-4-((4-nitronaphthalen-1-yloxy)methyl)pyridine
(4.50 g, 15.24 mmol) in MeOH (200 mL) and AcOH (200 mL) was passed
through a Thales H-cube (2.0 mL.min-1, 40° C., 55 mm 10% Pt/C
Cat-Cart, full hydrogen mode) and the volatiles were removed in vacuo.
The crude product was subjected to SCX capture and release and the
solvent was removed in vacuo to give
2-amino-4-((4-aminonaphthalen-1-yloxy)methyl)pyridine, (3.82 g, 94%) as a
purple solid: m/z 266 (M+H)+ (ES+).

[0213] A solution of CDI (4.18 g, 25.8 mmol) in DCM (15 mL) was added
dropwise under nitrogen to a solution of Intermediate A (5.91 g, 25.8
mmol) in DCM (15 mL) over 40 min. The resulting solution was stirred at
RT for 1 hr and was then added dropwise under nitrogen to a solution of
2-amino-4-((4-aminonaphthalen-1-yloxy)methyl)pyridine (3.80 g, 12.9 mmol)
in DCM and the mixture was stirred overnight. The volatiles were removed
in vacuo and the residue was purified by flash column chromatography
(SiO2, 120 g, MeOH in DCM, 0-6%, gradient elution) to give the tite
compound, Intermediate C, as an off white solid (4.27 g, 63%): m/z 521
(M+H)+(ES+).

[0215] To a stirred solution of 2-chloro-4-fluoropyridine (1.26 g, 9.58
mmol) and 4-amino-1-naphthol hydrochloride (750 mg, 3.83 mmol) in NMP (40
mL) at -20° C. was added potassium tert-butoxide (1.29 g, 11.50
mmol) and the reaction mixture then warmed to RT for 2.5 hr. The mixture
was diluted with water (100 mL) and extracted with EtOAc (100 mL and
2×80 mL) and the combined organic extracts were washed with brine
(150 mL), dried and evaporated in vacuo. The crude product was subjected
to SCX capture and release and the volatiles were removed in vacuo to
give 4-(2-chloropyridin-4-yloxy)naphthalen-1-amine as a brown solid (1.02
g, 92%): m/z 271 (M+H)+ (ES+).

[0216] To a stirred solution of
4-(2-chloropyridin-4-yloxy)naphthalen-1-amine (1.02 g, 3.76 mmol) in THF
(30 mL) at 0° C. was added DMAP (34 mg, 0.282 mmol) and then
di-tert-butyl dicarbonate (904 mg, 4.14 mmol). The reaction mixture was
stirred at 0° C. for 30 min and was then allowed to warm to RT.
After 1.5 hr the mixture was re-cooled to 0° C. and an additional
aliquot of di-tert-butyl dicarbonate (904 mg, 4.14 mmol) was added. The
resulting mixture was stirred at 0° C. for 15 min and at RT for 16
hr and was diluted with water (40 mL) and extracted with EtOAc
(2×40 mL). The combined organic extracts were washed with brine (75
mL), dried and evaporated in vacuo. The residue was purified by flash
column chromatography (SiO2, 80 g, 0-40% EtOAc in iso-hexane,
gradient elution) to give
4-(2-chloropyridin-4-yloxy)naphthalen-1-N,N-di-tert-butylcarbamate as a
purple solid (892 mg, 48%): m/z 471 (M+H)+(ES+).

[0218] To a stirred solution of tert-butyl
4-(4-(N,N-di-(tert-butyloxycarbonyl)amino)naphthalen-1-yloxy)pyridin-2-yl
carbamate (289 mg, 0.524 mmol) in DCM (8.0 mL), at 0° C., was
added TFA (4.0 mL) and the resulting mixture allowed to warm to RT. After
5 hr the volatiles were removed in vacuo and the residue was taken up in
MeOH (5.0 mL) and subjected to SCX capture. The volatiles were removed in
vacuo to provide 4-(4-aminonaphthalen-1-yloxy)pyridin-2-amine, (116 mg,
85%) as a brown-orange oil: m/z 252 (M+H)+ (ES+).

[0219] To a vigorously stirred mixture of Intermediate A (206 mg, 0.900
mmol) in DCM (20 mL) and saturated aq. NaHCO3 (14 mL) at 0°
C. was added trichloromethylchloroformate (325 μL, 2.70 mmol) in a
single portion and the stirring continued at 0° C. for 80 min. The
organic layer was separated and dried and was evaporated in vacuo to
provide 3-tert-butyl-5-isocyanato-1-p-tolyl-1H-pyrazole, as an orange
oil. This material was pumped under high vacuum for 30 min and was then
taken up into THF (6.0 mL) and the resulting solution kept under nitrogen
at 0° C. for use in the next step.

[0220] To a stirred solution of
4-(4-aminonaphthalen-1-yloxy)pyridin-2-amine, (116 mg, 0.462 mmol) and
DIPEA (240 μl, 1.39 mmol) in THF (3.0 mL) at 0° C. was added an
aliquot of the isocyanate solution prepared above (2.0 mL, 0.300 mmol)
and the resulting mixture allowed to warm to RT. Additional aliquots of
the isocyanate solution were added to the reaction mixture after 1.5 hr,
(1.0 mL, 0.150 mmol) and after a further 3.5 hr (0.5 mL, 0.075 mmol). The
mixture was maintained at RT for 20 hr and was then diluted with water
(30 mL) and was extracted with EtOAc (2×30 mL). The combined
organic extracts were washed with brine (50 mL), dried and then
evaporated in vacuo. The residue was purified by flash column
chromatography (SiO2; 12 g, 25-100% [5% MeOH in EtOAc] in
iso-hexane, gradient elution) to furnish the title compound Intermediate
D, as a brown oil (127 mg, 49%): m/z 507 (M+H)+(ES+).

[0227] The enzyme inhibitory activities of compounds disclosed herein were
determined by fluorescence resonance energy transfer (FRET) using
synthetic peptides labelled with both donor and acceptor fluorophores
(Z-LYTE, Invitrogen Ltd., Paisley, UK). Recombinant, phosphorylated p38
MAPKy (MAPK12:Invitrogen) was diluted in HEPES buffer, mixed with the
test compound at the desired final concentrations and incubated for 2 hr
at RT. The FRET peptide (2 μM) and ATP (100 μM) were added to the
enzyme/compound mixture and incubated for 1 hr. Development reagent
(protease) was added for 1 hr prior to detection in a fluorescence
microplate reader (Varioskan® Flash, ThermoFisher Scientific). The
site-specific protease cleaves non-phosphorylated peptide only and
eliminates the FRET signal. Phosphorylation levels of each reaction were
calculated using the ratio of coumarin emission (donor) over fluorescein
emission (acceptor) for which high ratios indicate high phosphorylation
and low ratios indicate low phosphorylation levels. The percentage
inhibition of each reaction was calculated relative to non-inhibited
control and the 50% inhibitory concentration (IC50 value) then
calculated from the concentration-response curve.

[0228] For the p38 MAPKa isoform (MAPK14: Invitrogen), enzyme activity was
evaluated indirectly by determining the level of
activation/phosphorylation of the down-stream molecule, MAPKAP-K2. The
p38 MAPKα protein was mixed with the test compound for 2 hr at RT.
The p38α inactive target MAPKAP-K2 (Invitrogen) and FRET peptide (2
μM), which is a phosphorylation target for MAPKAP-K2, and ATP (10
μM) were then added to the enzymes/compound mixture and the resulting
mixture incubated for 1 hr. Development reagent was then added and the
mixture incubated for 1 hr before detection by fluorescence completed the
assay protocol.

Cellular Potency Assays:

[0229] 1) LPS-induced TNFα/IL-8 Release in d-U937Cells

[0230] U937 cells, a human monocytic cell line, were differentiated to
macrophage-type cells by incubation with phorbol myristate acetate (PMA;
100 ng/ml) for 48 to 72 hr. Cells were pre-incubated with final
concentrations of test compound for 2 hr and were then stimulated with
0.1 μg/mL of LPS (from E. Coli: 0111:B4, Sigma) for 4 hr. The
supernatant was collected for determination of TNFα and IL-8
concentrations by sandwich ELISA (Duo-set, R&D systems). The inhibition
of TNFα production was calculated as a percentage of that achieved
by 10 μg/mL of BIRB796 at each concentration of test compound by
comparison against vehicle control. The relative 50% effective
concentration (REC50) was determined from the resultant
concentration-response curve. The inhibition of IL-8 production was
calculated at each concentration of test compound by comparison with
vehicle control. The 50% inhibitory concentration (IC50) was
determined from the resultant concentration-response curve.

2) LPS-Induced TNFα Release in THP-1 Cells

[0231] THP-1 cells, a human monocytic cell line, were stimulated with 3
μg/mL of LPS (from E. Coli; 0111:B4, Sigma) for 4 hr and the
supernatant collected for determination of the TNFα concentration
by sandwich ELISA (Duo-set, R&D systems). The inhibition of TNFα
production was calculated at each concentration by comparison with
vehicle control. The 50% inhibitory concentration (IC50) was
determined from the resultant concentration-response curve.

3) Poly I:C-Induced ICAM-1 Induction in BEAS2B Cells

[0232] Poly I:C (1 μg/ml) (Invivogene Ltd., San Diego, Calif.) was
transfected into BEAS2B cells (human bronchial epithelial cells, ATCC)
with Oligofectamine (Invitrogen, Carlsbad, Calif.). Cells were
pre-incubated with final concentrations of test compounds for 2 hr and
the level of ICAM1 expression on the cell surface was determined by
cell-based ELISA. At a time point 18 hr after poly I:C transfection,
cells were fixed with 4% formaldehyde in PBS and then endogenous
peroxidase was quenched by the addition of 0.1% sodium azide and 1%
hydrogen peroxide. Cells were washed with wash-buffer (0.1% Tween in PBS:
PBS-Tween). and after blocking the wells with 5% milk in PBS-Tween for 1
hr, the cells were incubated with anti-human ICAM-1 antibody (Cell
Signaling Technology, Danvers, Mass.) in 1% BSA PBS overnight at
4° C. The cells were washed with PBS-Tween and incubated with the
secondary antibody (HRP-conjugated anti-rabbit IgG, Dako Ltd., Glostrup,
Denmark). The ICAM-1 signal was detected by adding substrate and reading
the absorbance at 450 nm against a reference wavelength of 655 nm using a
spectrophotometer. The cells were then washed with PBS-Tween and total
cell numbers in each well were determined by reading absorbance at 595 nm
after Crystal Violet staining and elution by 1% SDS solution. The
measured OD 450-655 readings were corrected for cell number by dividing
with the OD595 reading in each well. The inhibition of ICAM-1 expression
was calculated at each concentration of test compound by comparison with
vehicle control. The 50% inhibitory concentration (IC50) was
determined from the resultant concentration-response curve.

MTT Assay: Cell Viability

[0233] Differentiated U937 cells were pre-incubated with each test
compound under two protocols: the first for 4 hr in 5% FCS and the second
in 10% FCS for 24 h. The supernatant was replaced with 200 μL of new
media and 10 μL of MTT stock solution (5 mg/mL) was added to each
well. After incubation for 1 hr the media were removed, 200 μL of DMSO
was added to each well and the plates were shaken lightly for 1 hr prior
to reading the absorbance at 550 nm. The percentage loss of cell
viability was calculated for each well relative to vehicle (0.5% DMSO)
treatment. Consequently an apparent increase in cell viability for drug
treatment relative to vehicle is tabulated as a negative percentage.

[0234] The in vitro profiles of the compound examples disclosed herein, as
determined using the protocols described above, are presented below
(Table 1).